PROJECT SUMMARY Recognizing the emotions of others guides our daily decisions. We perform actions that benefit others and suppress those that might cause harm or distress, even when it requires personal sacrifice. The recognition of a conspecific's distress and ability to alter ones behavior in light of that distress is disrupted in several psychiatric disorders (e.g., autism, psychopathy). Unfortunately, we know very little about the neurobiological substrates that control these functions because detailed work in animals at the single-unit and neurotransmitter level has not yet occurred. Recently, there have been a number of behavioral studies demonstrating that rodents can recognize conspecific distress and choose to alter behavior to alleviate that distress. Here, we propose to use cutting edge neuroscience techniques ? Designer Receptors Exclusively Activated by Designer Drugs (DREADDS), single-unit recording across multiple brain areas simultaneously, fast-scan cyclic voltammetry (FSCV), optogenetics, and calcium imaging ? to elucidate the neural mechanisms related to modification of reward-guided behavior during conspecific distress in multiple social contexts and time scales as contingencies are learned and social relationships change with experience. We propose a circuit by which behaviors are modulated by predicted social distress via interactions between basolateral amygdala (ABL), anterior cingulate cortex (ACC), nucleus accumbens core (NAc), and accumbal dopamine (DA) release. The dynamic relationship between areas within this circuit will be uncovered with precise spatial and temporal resolution during learning and long-term social interaction by recording from multiple brain areas simultaneously and determining if altered communication (DREADDS) between areas impacts behavior. Calcium imaging will allow us to monitor activity across single neurons and large groups of neurons over multiple days. We will jointly analyze images at different time instances and determine what is common across time points versus what has changed, and statistically determine how components correlate with behavior to determine how areas process social information at an internal network level. We predict that the ABL-ACC circuit is important for pairing recognition of conspecific distress with predictive stimuli and is necessary for correlates related to motivated behavior in NAc to be modified in social contexts. Furthermore, ACC will be more heavily involved in co-registering information pertaining to oneself and the conspecific, but is dependent on ABL during learning. We also theorize that DA release modulates predictive value signals in downstream targets such as NAc by reporting negative and positive prediction errors when rewards are accompanied by conspecific distress and shock avoidance. Finally, we propose experiments that will attempt to modulate pro- and anti-social behavior via optogenetic stimulation and inhibition of the DA system and by oxytocin administration, a novel therapeutic treatment for mental disorders characterized by social dysfunction.